A unique immunological compartment exists above the basal lamina of the intestine which consists of virtually only two cell types: the intestinal epithelial cell (IEC) and the intraepithelial lymphocyte (iIEL). the function of iIELs and their relationship with IECs is, however, largely unknown. Certainly the localization of the iIEL to the basolateral surface of the IEC to the virtual exclusion of other cell types, the oligoclonality of their T cell receptor (TCR) and dominant expression of CD8 suggests a role in immunosurveillance and/or immunoregulation. The preponderance of CD8 on iIELs strongly implicates major histocompatibility complex (MHC) class I-type molecules as counterligands on the IEC for iIEL-IEC interactions. To further define IEC-EL interactions, we have identified a molecule which is expressed on the cell surface of IECs as defined by several monoclonal antibodies (mAb) that, by several criteria, appears to be associated with {gp180}, MHC class Ia and, possibly, class Ib molecules. This molecule, the "34B1 antigen" is thus placed at a potentially critical functional location on the cell surface. Preliminary characterization of the 34B1 antigen shows the following distinctive features: (l) 34B1 is relatively restricted to expression by epithelial cells of the intestine, biliary tract, kidney, skin, thymus, granulocytes and activated T and B cells; (2) 34B1 is a 66- 70 kD glycoprotein with a high number of intrachain disulfide linkages; (3) 34B1 is involved in iIEL-IEC interactions as defined in a cell-cell adhesion assay; and (4) 34B1 coassociates with MHC class I molecules and (gpl80). These preliminary data strongly suggest a novel and important function for this molecule in the intestinal epithelial compartment. Our specific aims are: (1) to clone, sequence and identify the human and mouse 34B1 cDNA and gene; (2) to investigate the association of the 34B1 antigen with MHC class I by characterizing subunit associations in transfected mutant cell lines and COS cells; (3) to evaluate the functional consequences of 34B1 antigen ligation on IECs and iIELs and determine whether 34B1 functions in transduction of MHC class I signals; and (4) to determine the ligand for the 34B1 antigen.